Early-Phase Study to Assess Inhibitor Ribociclib in Patients With Recurrent Glioblastoma or Anaplastic Glioma

Preliminary evaluation of efficacy and determination of the ribociclib safety profile in
patients with brain tumors will be studied. All patients will be treated with ribociclib (600
mg/day) for 8-21 days before surgical resection of the recurrent tumor. Rb status of the
recurrent tumor will be determined by immunohistochemistry within 2 weeks after surgery.
Patients with Rb-positive tumors will continue treatment with ribociclib (21 days on, 7 days
off) after surgery. Patients will be treated until unacceptable toxicity is observed, or
until disease progression as assessed by radiographic or clinical metrics. We will determine
whether molecular markers associated with changes induced by ribociclib treatment in tumors
(matching initial vs. recurrent tumors) correlate with progression-free survival.

Approximately 20% of patients with recurrent high-grade glioma will undergo surgical
resection of their tumor typically at the time of first recurrence. These patients will be
eligible for this study. An extra 10 mL of blood will be collected during a routine clinical
procedure prior to initiation of ribociclib treatment (i.e., baseline blood sample),
separated into plasma and buffy coat fractions, and frozen for pharmacokinetic (PK) analysis.
Patients will be treated with ribociclib for 8-21 days prior to surgery to identify drug
effects on tumor cells, and to determine drug PK. The last presurgical dose of ribociclib
will be administered on the day of surgery at 4-8 hours prior to surgery to allow sufficient
time for the drug to enter tumor cells, inhibit CDK4/6, and modulate downstream effectors.
Blood will be acquired within 1 hour before surgery (as close to the time of surgery as
possible). Blood will be separated into plasma and buffy coat fractions, and frozen. During
surgery, samples of brain tumor core and infiltrating brain tumor will be acquired. Tissue
samples will be frozen or fixed in paraffin embedded blocks and histology for PK and
molecular analyses.

Inclusion criteria:

- Written informed consent must be obtained prior to any screening procedures

- Patients age 18-85 are eligible for study participation

- History of grade III or IV glioma (GBM or AG) with archived FFPE and/or frozen tumor
tissue available

- Patient must be a candidate for surgical resection of recurrent high-grade glioma

- Karnofsky Performance Scale score ≥ 70.

- Life expectancy of 4 months or longer.

- Received at least 1 prior systemic therapy for glioma.

- A sufficient interval must have elapsed between the last dose of prior anti-cancer
therapy (including cytotoxic and biological therapies and major surgery) and
enrollment, to allow the effects of prior therapy to have abated

- Patients must have adequate organ function

- For continued ribociclib treatment after surgery, immunohistochemical (IHC)
confirmation of Rb expression in ≥50% of malignant tumors cells in at least 1 tumor
specimen is

Exclusion criteria:

- Impairment of gastro-intestinal (GI) function or GI disease that may significantly
alter the absorption of ribociclib such as patients with a history of GI surgery which
may result in intestinal blind loops and patients with clinically significant
gastroparesis, unresolved nausea, vomiting, or diarrhea of CTCAE grade > 1

- Impaired cardiac function or clinically significant cardiac diseases

- Patients who are currently receiving treatment (within 5 days prior to starting study
drug) with agents that are metabolized predominantly through CYP3A4 and that have a
narrow therapeutic window. Agents including vitamins, supplements, and herbal
supplements that are either (i) metabolized solely through CYP3A4/5, CYP1A2 or BSEP
and have a narrow therapeutic window or (ii) are strong inhibitors of CYP3A4/5, CYP1A2
or BSEP. Agents that are known strong inducers or inhibitors CYP3A4 are prohibited.
Patients must avoid consumption of grapefruit, Seville oranges or products containing
the juice of each during the entire study and for 7 days before the first dose.

- Patients with concurrent severe and/or uncontrolled concurrent medical conditions that
the investigator believes could compromise participation in the study (e.g.,
uncontrolled hypertension and/or diabetes mellitus, clinically significant pulmonary
disease, clinically significant neurological disorder, active or uncontrolled
infection)

- Pregnant or lactating women, where pregnancy is defined as the state of a female after
conception and until the termination of gestation, confirmed by a positive hCG
laboratory test (> 5 mIU/mL).

- Women of childbearing potential, defined as all women physically capable of becoming
pregnant, unless they are using effective methods of contraception during dosing of
study treatment. Effective contraception must be used by both sexes (female patients
and their male partners) during study treatment and for 30 days after the last dose of
study medication

- Fertile males must be willing to use contraception. Fertile males must use condom with
spermicide (double barrier method). Effective contraception, as defined above, must be
used by both sexes (male patients and their female partners) during study treatment
and for 30 days after the last dose of study medication. A condom is required to be
used by vasectomized men in order to prevent delivery of the study drug via seminal
fluid.

- Patients unwilling or unable to comply with the protocol

- Known diagnosis of human immunodeficiency virus (HIV) or hepatitis C (testing is not
mandatory)